The migration, or "translocation", of protons in biological systems is a phenomenon of fundamental importance to such biological processes as viral replication, ATP synthesis, enzyme catalysis, the maintenance of pH gradients, proton pumping, and photosynthesis. From the computational point of view, however, the modeling of proton translocation represents a particularly difficult challenge-most notably because of the many complex interactions involved, the fact that bonding topologies are continually evolving due to the proton hopping between molecular groups, and the overall structural complexity of the biomolecular systems of interest. In most instances, the primary conceptual question is whether Nature utilizes and "guides" the postulated proton shuttling characteristics of hydrogen bonded water units and/or whether specific protein residues chemically participate in the proton translocation process in certain key biomolecules. In this renewal proposal, an ongoing and unique computer simulation strategy is described for the study of proton translocation in general biomolecular systems. Specific applications of the approach include the M2 proton channel in the influenza A virus, synthetic leucine-serine proton channels, the enzyme carbonic anhydrase, and the proton pump cytochrome c oxidase. The overall research plan is made possible by a novel and accurate Molecular Dynamics simulation approach which allows for explicit proton transport through water molecules and ionizable amino acid residues in hydrogen bonded networks. A key target in the research will be to reveal the underlying microscopic biomolecular interactions which influence proton translocation in the above mentioned systems, as well as the way in which structural and chemical modifications can affect this important property. The proposed research also adds a new overall dimension to the field of biomolecular computer simulation.